Pain Management

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience. Acute pain lasts < 3 months and typically has a specific, identifiable cause. Chronic pain lasts > 3 months and may exist in the absence of tissue damage or after healing would have been expected to occur. Pain management involves a combination of addressing underlying causes and using a systematic approach tailored to the clinical scenario.

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Definitions and Physiology

Definitions

  • Nociception: process through which peripheral receptors transmit information about current (or potential) tissue damage centrally as pain
  • Nociceptor: receptor in end-organ that detects biochemical changes associated with current or potential tissue damage
  • Nociceptive pain: pain caused by actual or threatened damage to non-neural tissue
  • Neuropathic pain: pain caused by pathology in the somatosensory nervous system
  • Central sensitization: increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold input
    • Allodynia: pain due to a stimulus that does not typically provoke pain
    • Hyperalgesia/hyperpathia: heightened response to a typically painful stimuli

Physiology

  • Complex bidirectional process with phases: transduction → transmission → modulation → central perception
  • Peripheral nerves, both motor and sensory, are grouped by size and myelination. 
  • Pain is experienced in 2 phases:
    1. First phase is mediated by the fast-conducting A-delta fibers, associated with an initial extremely sharp pain.
    2. Second phase is mediated by C fibers, associated with a more prolonged and a less intense feeling of pain.
  • Type-A fibers: large and myelinated, thus fast conducting
    • A alpha:
      • Primary receptors of the muscle spindle and Golgi tendon organ
    • A beta: 
      • Largest-diameter afferent axon
      • Secondary receptors of the muscle spindle, contribute to cutaneous mechanoreceptors
      • Perceive light touch and/or moving stimuli
    • A delta: 
      • Free nerve endings that conduct stimuli related to pressure and temperature
      • Action potential conducts at a rate of approximately 20 m/s towards the central nervous system (CNS)
    • A gamma: 
      • Motor neurons that control the intrinsic activation of the muscle spindle
  • Type-B fibers:
    • Middle-sized, thinly myelinated fibers
    • Responsible for autonomic information
  • Type-C fibers:
    • Unmyelinated nociceptor slow fibers (conduct at a rate of approximately 2 m/s)
    • Respond to combinations of thermal, mechanical, and chemical stimuli

Types of Pain

Types of pain according to duration
TypeDurationCharacteristic
Acute pain< 3 months
  • Usually related to tissue damage
  • Improves with resolution of injury
  • Associated with autonomic protective reflexes (e.g., muscle spasm or “splinting”)
Chronic pain> 3 months
  • Pain that extends beyond expected period of healing
  • Pathology usually insufficient to explain the presence or extent of the pain
  • Disrupts sleep, daily activities, and psychosocial function
Types of pain according to quality
Nociceptive painTypically acute
  • The result of direct stimulation of nociceptors and normal neural signaling to the brain
  • May be due to tissue damage or threat of potential damage at nociceptor
  • Characteristics vary based on nociceptor type/location
  • Somatic: easy to localize, perceived by nociceptors located on the skin or in musculoskeletal tissues (e.g., fracture, burns)
  • Visceral: poorly localized, perceived by nociceptors found in organ systems (e.g., pancreatitis, myocardial infarction)
Neuropathic painVariable, often chronic
  • Due to nerve damage or aberrant pain processing
  • Described as burning, tingling, or shock-like, distributed along the path of nerves or nerve roots
  • Usually presents with hyperpathia, allodynia, and sensory deficit
  • Examples: pain associated with herpetic neuralgia, sciatica, neoplasias, diabetic neuropathy, phantom pain, etc.
Nociplastic pain (recently defined)Usually chronic or intermittent
  • Altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain
  • Examples: fibromyalgia, complex regional pain syndrome, chronic low back pain, irritable bowel syndrome, bladder pain syndrome

Management of Pain

General principles

  • Must be tailored to each patient’s circumstances, perspective, and physiologic condition
  • Requires a systematic assessment and regular reassessments:
    • Type: throbbing, cramping, burning, stabbing, etc.
    • Periodicity: continuous, with or without exacerbations or incident
    • Location
    • Intensity (may be determined with a visual analog scale)
    • Modifying factors
    • Effects of treatments
    • Functional impact
    • Impact on patient
  • Whenever possible, use targeted, disease-specific treatment.
  • Incorporate non-pharmacologic adjuncts and maximize the use of non-opioid analgesics before the use of opioids. 
  • If an opioid is prescribed for pain:
    • Use short-acting agents only
    • Use for the shortest duration possible 
    • Screen for risk of opiate misuse
    • Utilize local prescription monitoring program
    • Counsel patients on safe storage and disposal

Management of chronic pain

The following principles are recommended by the World Health Organization (WHO) as a basis for the treatment of chronic pain:

  • “By the clock”: Analgesics should be given at regular intervals. The frequency depends on whether it is a long- or short-acting preparation. 
  • “By the mouth”: If possible, drugs should be administered orally. If the oral route is not feasible, the least invasive route should be considered (e.g., sublingual or subcutaneous before IV). 
  • “By the ladder”: Stick to the 3-step system (see figure below). Drug selection should be appropriate to the severity of the pain. With severe pain, it may be appropriate to begin at the top of the ladder with a strong opioid. It is usually not necessary to step down unless the cause of pain is believed to have resolved. 
  • “By the individual with attention to details”: Dosing of pain medication should be adapted to the individual, as every patient responds differently. To optimize adherence and outcomes, the patient and those who care for them should be provided with a written program.
Analgesic ladder for cancer pain diagram with steps

Analgesic ladder for cancer pain

Image by Lecturio.

Most commonly used substances

  • Non-opioid medications
    • Nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, naproxen)
    • Acetaminophen
    • Aspirin
  • Weak opioids
    • Codeine 
    • Tilidine
    • Dihydrocodeine 
    • Tramadol (depending on the dose, tramadol can also behave as a strong opioid)
  • Strong opioids 
    • Pethidine 
    • Morphine 
    • Oxycodone 
    • Methadone
    • Hydromorphone 
    • Buprenorphine
    • Fentanyl 
  • Adjuvant analgesics (for specific indications)
    • Alpha-2 adrenergic agonists (e.g., clonidine, tizanidine): support effect of opioids, allow for reduction of opioid dosages in acute postoperative pain, chronic pain, neuropathic pain
    • Anticonvulsants (e.g., gabapentin, phenytoin, carbamazepine, pregabalin): e.g., neuropathic pain (especially trigeminal neuralgia)
    • Antidepressants (tricyclics, serotonin-norepinephrine reuptake inhibitors (SNRIs)): e.g., neuropathic pain, cancer pain, migraine, tension headache, postherpetic neuralgia
    • Beta-blockers (metopropolol, propanolol, timolol): prevention of migraine headaches
    • Bisphosphonates: e.g., cancer-related bone pain, osteoarthritis
    • Botulinum toxin: refractory chronic pain, especially trigeminal neuralgia, postherpetic neuralgia, migraine
    • Cannabis and cannabinoids (e.g., nabiximols, dronabinol, nabilone): e.g., cancer pain
    • Corticosteroids: e.g., neuropathic pain, bone pain, headache caused by increased intracranial pressure 
    • N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine): e.g., acute pain, perioperative pain
    • Topical agents (e.g., lidocaine, capsaicin, diclofenac patch, ketamine cream, gabapentin cream): regional neuropathic pain

Approach to specific types of pain

Nociceptive pain
  • Ideal treatment: Remove underlying cause (initial analgesics should be administered in tandem with diagnostic tests).
  • Pharmacologic therapy follows the WHO 3-step approach involving non-opioid analgesics, mild opioids, and strong opioids, with or without adjuvants.
  • 1st step: non-opioid analgesics (NSAIDs, aspirin, acetaminophen). Keep in mind the ceiling effect of non-opioids (no additional analgesic effect beyond a certain dose).
  • 2nd step: if non-opioid analgesics are insufficient → opioid analgesics
    • Non-opioid and opioid analgesics have additive effects and can be combined.
    • Must screen for risk of opioid use disorder
    • Long-term opioid use is reserved for cancer-related or end-of-life pain.
    • In cases of extreme pain, patient-controlled analgesia is used.
  • In the case of chronic pain, both emotional and organic factors should be assessed before initiating therapy.
  • Adjuvant therapy options other than traditional analgesics: antidepressants, anticonvulsants
Neuropathic painIf possible, identify and correct mechanical nerve compression via physical therapy and/or surgery.
First-line:
  • Antidepressants
  • Anticonvulsants
  • Topical analgesic therapy (e.g., lidocaine, NSAIDs, capsaicin)
Second-line:
  • Strong opioids
  • NMDA receptor antagonists (e.g., ketamine)
  • Muscle relaxants (e.g., tizanidine, baclofen)
Third-line:
  • Cannabinoids
  • Botulinum toxin
  • Intrathecal ziconotide
Fourth-line:
  • Electrical nerve stimulation
  • Sympathetic nerve blocks
  • Steroid injections
Non-pharmacological treatmentsTo be used as a first-line measure or as an adjunct in multimodal pain management:
  • Physical therapy
  • Cognitive-behavioral therapy
  • Acupuncture
  • Heat and/or cold application
  • Transcutaneous electrical nerve stimulation (TENS)
  • Massages, positioning, and repositioning
  • Relaxation and mindfulness-based stress reduction
  • Breathing techniques
  • Distraction, guided imagery, and/or biofeedback
  • Music therapy
  • Occupational therapy

References

  1. Dennis L. Kasper et. al. (2015). Harrison’s Principles of Internal Medicine. Chapter 18: Pain: Pathophysiology and Management, Part 2: Cardinal Manifestations and Presentation of Diseases, Section 1: Pain, page 8795.
  2. David Tauben, MDBrett R Stacey, MD. Approach to the management of chronic non-cancer pain in adults. UpToDate. Retrieved September 9, 2020, from https://www.uptodate.com/contents/approach-to-the-management-of-chronic-non-cancer-pain-in-adults?search=overview-of-the-treatment-of-chronic-non-cancer-pain&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  3. Pratik Pandharipande, MD, MSCIStuart McGrane, MBChB. Pain control in the critically ill adult patient. UpToDate. Retrieved September 9, 2020, from https://www.uptodate.com/contents/pain-control-in-the-critically-ill-adult-patient?search=pain%20management&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4
  4. Russell K Portenoy, MD, Zankhana Mehta, MD, Ebtesam Ahmed, PharmD, MS. Cancer pain management: General principles and risk management for patients receiving opioids. UpToDate. Retrieved September 9, 2020, from https://www.uptodate.com/contents/cancer-pain-management-general-principles-and-risk-management-for-patients-receiving-opioids?search=pain%20management&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8
  5. UpToDate. Search: overview-of-the-treatment-of-chronic-non-cancer-pain. Retrieved September 9, 2020, from https://www.uptodate.com/contents/evaluation-of-chronic-pain-in-adults?source=history_widget
  6. COUNCIL, I. (2001). Pain: Current Understanding of Assessment, Management, and Treatments. https://www.npcnow.org/system/files/research/download/Pain-Current-Understanding-of-Assessment-Management-and-Treatments.pdf
  7. Owen GT, Bruel BM, Schade CM, Eckmann MS, Hustak EC, Engle MP. Evidence-based pain medicine for primary care physicians. Proc (Bayl Univ Med Cent). 2018;31(1):37-47. Published 2018 Jan 8. doi:10.1080/08998280.2017.1400290. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903506/

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